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Biomedical subjects

T P Jacobs

Publications and source records attributed to T P Jacobs.

At least 37 records · Page 2Linked to original sources
PubMed1987

Clodronate. A randomized study in the treatment of cancer-related hypercalcemia.

Malignancy-associated hypercalcemia is a common and recalcitrant problem. Current modes of therapy are often ineffective or prohibitively toxic. Clodronate disodium is a diphosphonate capable of inhibiting bone resorption resulting in a hypocalcemic effect. In this randomized, placebo-controlled study, we investigated the effect of hydration only (Rx-1) vs the effect of hydration plus either intravenously administered clodronate disodium, 4 mg/kg of body weight per day for three days (Rx-2) or intravenously administered clodronate disodium, 12 mg/kg of body weight given once only (Rx-3). By the third day of observation, Rx-2 produced a significant 2.8 mg/dL (0.70 mmol/L) reduction in serum calcium levels, whereas Rx-1 and Rx-3 did not produce a significant hypocalcemic effect when compared with baseline values. There were no toxicities observed. Intravenously administered clodronate appears to be an excellent agent for the acute treatment of malignancy-associated hypercalcemia.

Adult↗
PubMed1987

Increased thromboxane A2 and 5-HETE production following spinal cord ischemia in the rabbit.

Ischemia was induced for 25 min in the spinal cord of rabbits followed by a long term period of recirculation. At various time points of recirculation (5, 30 min, 4, 18 hr and 1 wk) slices were taken from the ischemic region and incubated for 45 min in Krebs-Ringer solution. The levels of the eicosanoids, PGE2, PGD2, PGF2 alpha, TXB2, 6-keto-PGF1 alpha and 5-HETE accumulated in the incubation medium were measured by radioimmunoassay. TXB2, release was found to be increased at an early (5 min) and late (1 wk) period of reperfusion. A seven-fold increase in the release of 5-HETE was found 5 min after reperfusion that tended to stay elevated at 18 hr and 1 week of recirculation. PGI2 synthetase activity decreased by 40% at 30 min, with return to normal at later time points. The ratio of TXA2/PGI2 was significantly higher than control at 30 min and 1 wk. The synthesis of PGE2, PGD2 and PGF2 alpha was maintained at normal levels throughout the complete course of reperfusion. No changes in eicosanoid synthesis were noted in remote spinal cord regions. The significant increase of TXA2 synthesis at 5 min and 1 wk of reperfusion may point to a role of this arachidonate metabolite in the acute events and in the later stages of neurological dysfunction. The enhanced release of 5-HETE, a metabolite of 5-HETE, suggest an enhanced formation of leukotriene B4 and peptide leukotrienes and a potential role for these 5-lipoxygerase metabolites of arachidonate in ischemia injury to the brain and the spinal cord.

Animals↗
PubMed1987

Prostaglandin derivative PGBx improves neurologic recovery after ischemic spinal injury.

Neurological dysfunction resulting from an ischemic insult in the central nervous system (CNS) is believed to be an indirect outcome of impaired energy production. Recent studies suggest that prostaglandin Bx (PGBx), an oligomer of PGB1 and 15-keto-PGB1, may be beneficial in protecting mitochondrial function after ischemic insults by preventing uncoupling of oxidative phosphorylation. In the present study, PGBx had a significant influence on neurological outcome after ischemic injury in the rabbit spinal cord. These findings suggest that PGBx may be beneficial in the treatment of CNS ischemic injuries.

Animals↗
PubMed1987

Thromboxane and 5-HETE increase after experimental spinal cord injury in rabbits.

Eicosanoids are known mediators of inflammation, vascular permeability, and are involved in microcirculatory blood flow regulation. To study their potential involvement in the pathophysiology of CNS trauma we used a rabbit spinal cord trauma model. Rabbits were subjected to lumbar spinal cord trauma produced by a modification of the Allen weight-drop method. TXB2, 6-keto-PGF1 alpha, PGE2, and 5-hydroxyeicosatetraenoic acid (5-HETE) release from spinal cord slices incubated ex vivo were measured by radioimmunoassay at 5, 30 min, 24 hrs, and 2 wks after trauma. Five and 30 min after trauma the TXB2/6-keto-PGF1 alpha ratio was elevated and the release of 5-HETE at 5 min after trauma increased in the injured spinal cord whereas release of 6-keto-PGF1 alpha and PGE2 remained at base-line levels. In the thoracic spinal cord, TXB2 and 6-keto-PGF1 alpha release were increased at 30 min after trauma. Release of 5-HETE from the injured spinal cord was also elevated 24 hrs after trauma. Two wks after trauma, TXB2 and 6-keto-PGF1 alpha release were also elevated in the injured spinal cord. Measurements of tissue water content by microgravimetry indicated progressive edema in the injury site while histopathological evaluation indicated progressive damage and tissue destruction. The results of this study suggest that eicosanoids may be involved in the pathophysiology of spinal cord trauma through two potential mechanisms: 1) site specific increase in the TXB2/6-keto-PGF1 alpha ratio immediately following trauma which is due primarily to an increase in TXA2 synthesis; 2) the increase synthesis of 5-HETE which signals the activation of the 5-lipoxygenase pathway of arachidonate metabolism and production of mediators that are involved in inflammatory mechanisms and may affect local blood flow regulation and blood-spinal cord barrier integrity.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Dichloromethylene diphosphonate action in hematologic and other malignancies.

We have studied the administration of both oral and intravenous dichloromethylene diphosphonate (Cl2MDP) in patients with hypercalcemia and/or hypercalciuria due to increased bone resorption in the setting of multiple myeloma (N = 16) or chronic lymphocytic leukemia (N = 1). The effectiveness of 1600 mg of oral Cl2MDP twice daily was studied in 14 subjects with refractory multiple myeloma, active osteolytic disease and either persistent hypercalciuria (urinary Ca greater than 200 mg per g creatine on a low Ca intake) or hypercalcemia (serum Ca greater than 11.0 mg/dl), in a double-blind, placebo-controlled, 16 week-long trial. Of the 12 patients who received Cl2MDP (2 died in the placebo phase), 11 had marked reductions in urinary calcium (P less than 0.001), which fell into the normal range in 9. Urinary hydroxyproline decreased significantly in 8. Eight of the 11 responders also appeared to have decreases in bone pain associated with Cl2MDP therapy. Similar results were found when this protocol was used in a study of 10 women with breast cancer metastatic to bone. In addition, intravenous Cl2MDP was studied in 12 patients with hypercalcemia of malignancy, of whom 2 had multiple myeloma and 1 had chronic lymphocytic leukemia (CLL) associated with extensive osteolytic bone destruction. We gave 2.5 mg/kg on the first treatment day and 5 mg/kg daily thereafter for up to six more days. Serum calcium fell to normal after a mean of four days in the three patients with hematologic malignancies as well as in eight of the nine with solid tumors. Both urinary Ca and OHP also declined significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Endogenous opioid immunoreactivity in rat spinal cord following traumatic injury.

It has been postulated that endogenous opioids play a pathophysiological role in spinal cord injury, based on the therapeutic effects of the opiate receptor antagonist naloxone in certain experimental models. The high doses of naloxone required to exert a therapeutic action suggest that naloxone's effects may be mediated by non-mu opiate receptors, such as the kappa receptor. This notion is supported by recent pharmacological studies demonstrating that an opiate antagonist more active at kappa sites is effective and far more potent than naloxone in improving outcome after spinal cord injury. Moreover, dynorphin--postulated to be the endogenous ligand for the kappa receptor--is unique among opioids in producing hindlimb paralysis following intrathecal administration in the rat. In the present studies we have examined changes in endogenous opioid immunoreactivity following traumatic spinal cord injury in the rat. Dynorphin A was found to increase progressively with graded injury; changes were restricted to the injury segment and adjacent areas and were time dependent. Dynorphin A-(1-8) showed no marked changes. Methionine and leucine enkephalin were either unaltered or reduced at the injury site; changes were not well localized and were not clearly related to the injury variables. These findings provide further support for a potential pathophysiological role of prodynorphin-derived peptides in spinal cord injury.

Animals↗
PubMed1985

Effects of traumatic injury on dynorphin immunoreactivity in spinal cord.

Traumatic spinal cord injury in rats resulted in a significant eleation of dynorphin A immunoreactivity in spinal cord tissue at the level of, and below, the site of injury. [Leu5]enkephalin levels in the same tissue samples were not significantly altered following severe injury. Dynorphin A immunoreactivity was found in the fraction relatively enriched in synaptosomes after subcellular fractionation of spinal cord tissue. The dynorphin A content of this fraction was not significantly changed following injury, suggesting that dynorphin containing nerve terminals and axons are not severely damaged as a result of the injury.

Animals↗
PubMed1985

Changes in substance P and somatostatin in the spinal cord after traumatic spinal injury in the rat.

Immunoreactive substance P (SPI) and somatostatin (SOMI) are found in spinal cord but their physiological roles remain speculative. Several classes of neuropeptides, including endogenous opioids and thyrotropin-releasing hormone (TRH), have been implicated in the pathogenesis or recovery from spinal cord injury. In the present studies, changes in SPI and SOMI were examined in the spinal cord after traumatic injury in the rat. Both peptides showed time-dependent, localized decreases at the injury site, which were statistically related to the degree of post-traumatic neurological dysfunction. Such changes differ from those of a number of other peptides after spinal injury and suggest that substance P and/or somatostatin may play a role in the secondary pathophysiological responses which follow trauma to the spinal cord.

Animals↗
PubMed1985

Increased dynorphin immunoreactivity in spinal cord after traumatic injury.

Opiate antagonists, at high doses, have been shown to improve physiological variables and outcome after experimental spinal injury. Dynorphin appears to be unique amongst opioids in producing hindlimb paralysis after intrathecal injection. Taken together, these findings suggest a possible pathophysiological role for endogenous opioids, particularly dynorphin, in spinal injury. In the present studies we examined the relationship between changes in dynorphin immunoreactivity (Dyn-ir) in rat spinal cord after traumatic injury and the subsequent motor dysfunction. Trauma was associated with significantly increased Dyn-ir at the injury site, but not distant from the lesion. Dyn-ir was found elevated as early as 2 h and as late as 2 weeks after trauma, and was significantly correlated with the degree of injury. These data are consistent with the hypothesis that dynorphin systems may be involved in the secondary injury that follows spinal trauma.

Animals↗
PubMed1985

Motor dysfunction after spinal cord injury is mediated by opiate receptors.

Naloxone, an opiate receptor antagonist, improves neurological outcome following traumatic cervical spinal cord injury in the cat and ischemic lumbar spinal cord injury in the rabbit. However, the doses of naloxone required have been quite high (greater than 1 mg/kg), suggesting that its beneficial actions are either not opiate receptor mediated or mediated by non-mu opiate receptors (which are less naloxone-sensitive). The kappa receptor appears to be the predominant opiate receptor in the spinal cord in a variety of species. For these reasons we evaluated the effects of a somewhat kappa selective opiate receptor antagonist WIN44,441-3 [WIN(-)] on neurological recovery following traumatic spinal injury in the cat and ischemic spinal injury in the rabbit. Animals treated with this more selective antagonist showed improved motor recovery as compared with animals treated with either physiological saline or with the dextroisomer of the WIN compound [WIN44,441-2; WIN(+)]. These findings support the hypothesis that motor dysfunction after spinal cord injury is in part mediated by opiate receptors and indicate that kappa selective opiate receptor antagonists may have particular therapeutic utility in spinal cord injury.

Animals↗
PubMed1985

Opiate antagonist WIN44,441-3 stereospecifically improves neurologic recovery after ischemic spinal injury.

In the unanesthetized rabbit, temporary aortic occlusion results in predictable patterns of spinal cord injury. We use this "spinal stroke" model to assess the potential role of opiate antagonists in treating CNS ischemia. WIN44,441-3 (WIN(-], an opiate antagonist with enhanced activity at the kappa-receptor, reduced motor dysfunction after ischemic spinal cord injury. The effect was stereospecific and dose-related; beneficial actions were seen at doses as low as 40 micrograms/kg. Opiate receptor antagonists may be therapeutically useful in ischemic CNS injury, and the beneficial actions of these compounds may be at the kappa-receptor site.

Animals↗
PubMed1985

Effect of TRH analogs on neurologic recovery after experimental spinal trauma.

Effects of two stable TRH analogs were compared after experimental spinal trauma in cats. CG3509, which has a substitution at the amino-terminus of the peptide, improved neurologic recovery; MK771, which has modifications at both ends of the tripeptide, was ineffective. These findings indicate that TRH analogs may be of use in spinal cord injury, and suggest that the C-terminal amino acid may be critical for the beneficial effects of TRH or TRH-analogs in CNS injury.

Animals↗
PubMed1984

Naloxone in experimental spinal cord ischemia: dose-response studies.

Temporary aortic occlusion produces a consistent degree of spinal cord injury in the unanesthetized rabbit. This 'spinal stroke' model was utilized to examine the potential therapeutic effects of the opiate antagonist naloxone in central nervous system ischemia. Naloxone treatment resulted in dose-related enhancement of motor recovery; greatest functional recovery was observed in rabbits treated with a dose of 2 mg/kg per h. This dose compares well with the high doses of naloxone shown to have a beneficial effect in other experimental models of stroke and spinal injury. In contrast, clinical stroke studies, which have been largely unsuccessful, have utilized naloxone doses which are several orders of magnitude lower than those successfully employed in experimental models.

Animals↗
PubMed1984

Dynorphin-related peptides cause motor dysfunction in the rat through a non-opiate action.

We compared effects on motor function of four peptides belonging to the dynorphin family--dynorphin-(1-17) (DYN-(1-17], dynorphin-(1-13) (DYN-(1-13], dynorphin-(1-8) (DYN-(1-8] and alpha-neo-endorphin (alpha NE). After intrathecal administration, each of these peptides produced dose-related, flaccid, hindlimb paralysis, with the order of potency being DYN-(1-17) greater than DYN-(1-13) greater than alpha NE congruent to DYN-(1-8). This motor dysfunction was not reversed or blocked by the opiate receptor antagonist naloxone and was not produced by a variety of other kappa-selective agonists. However, paralysis was produced by des-Tyr-dynorphin (DYN-(2-17], which does not act at the opioid receptor. Taken together, the present studies show that dynorphin-related peptides, uniquely amongst opioids, produce motor dysfunction, an action which does not appear to be mediated by opioid receptors.

Animals↗
PubMed1984

Thyrotropin-releasing hormone in experimental spinal injury: dose response and late treatment.

Early treatment with thyrotropin-releasing hormone (TRH) at high doses improves neurologic recovery from experimental spinal injury in cats. We have now compared the effects of TRH dose and time of treatment on neurologic outcome. TRH-treated animals showed better motor recovery than saline controls; effects were dose-related (between 0.02 mg/kg/hr and 2.0 mg/kg/hr), with significant effects even at the lowest dose. Cats treated at 24 hours after injury also improved significantly. These findings provide additional support for TRH trials in human spinal injury and suggest that even late treatment may be effective.

Animals↗
PubMed1984

Megadose corticosteroid therapy following experimental traumatic spinal injury.

Corticosteroids are frequently used in the treatment of spinal trauma, although neither experimental nor clinical evidence to support their use is persuasive. Recently there have been claims that extremely high doses ("megadoses") of corticosteroids (equivalent to 15 to 30 mg/kg of methylprednisolone) improve neurological recovery compared to results with traditional steroid doses. The authors have compared the effect of megadose dexamethasone and methylprednisolone therapy to that of saline treatment following traumatic cervical spinal injury in the cat. During 6 weeks postinjury, neurological recovery did not differ significantly in corticosteroid-treated and saline-treated animals. Moreover, histopathological changes in the spinal cord were similar in methylprednisolone- and saline-treated cats. Corticosteroid-treated animals had a higher mortality rate than did control animals, with the predominant cause of death being neurogenic pulmonary edema. It is concluded that megadose corticosteroid treatment does not improve neurological recovery in this experimental model of spinal injury, and is associated with increased mortality.

Animals↗
PubMed1984

Evaluation of the calcium channel antagonist nimodipine in experimental spinal cord ischemia.

The potent, centrally active, calcium channel antagonist, nimodipine, was utilized in a highly predictive "spinal stroke" model in order to investigate the potential pathophysiological effects of calcium flux in spinal injury, as well as to evaluate the potential therapeutic role of the newly developed dihydropyridine derivatives in ischemic central nervous system injury. Nimodipine, administered before or after ischemia, at doses shown to be effective in improving cerebral blood flow and in dilating central blood vessels, failed to improve either the histopathological changes or the functional deficit caused by temporary aortic occlusion in the unanesthetized rabbit.

Animals↗